Dawson et al, 2013, NEJM “Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer” reported that circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). These observations are consistent with the view that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer.
But cell-free DNA is very short, which greatly affects sensitivity. Tsui et al, 2012, PLOS ONE, “High Resolution Size Analysis of Fetal DNA in the Urine of Pregnant Women by Paired-End Massively Parallel Sequencing” reported that the median DNA target size in plasma is 168 base pairs (bp). The median DNA target sizes in urine were 29 by to 45 base pairs.
Additionally, next generation sequencing (NGS) has an accuracy rate of 99.7%, and so an error rate of 0.3% which greatly affects sensitivity and specificity, especially for biological samples wherein a mutant nucleic acid sequence of interest is present with a much higher number of non-mutant (wild type) sequences. For example, there are reports that even using hybridization-based enrichment, the best sensitivity is 1 mutant per 2500 wild type molecules (0.04%) which is difficult to reach in practice and still too high if combined with an error rate of 0.3%.